Effect of Music Therapy on Parent-Infant Bonding Among Infants Born Preterm

Key Points Question What is the effect of parent-led, infant-directed singing—initiated in the neonatal intensive care unit with support from a music therapist and extending 6 months after discharge—on parent-infant bonding at 6 and 12 months’ infant-corrected age? Findings In this randomized clinical trial involving 213 families, mothers engaging in parent-led, infant-directed singing reported similar parent-infant bonding at 6 and 12 months’ corrected age as mothers receiving standard care only. Meaning These results suggest that, although safe and accepted by parents, parent-led, infant-directed singing was no more effective at improving mother-infant bonding than standard care.

sung or toned voice to pacify the infant, promote state regulation, and enable bonding, by using simple melodies or modifying songs of kin [21] into a lullaby style matched to infant responses. Use of sung/toned voice is adjusted in response to infant engagement/disengagement cues. The infant may be resting in his/her isolette with the portal door open, resting swaddled in his/her basinet or bed, or swaddled and cradled in a static manner by the caregiver (consistent with Kangaroo care) or the therapist. MT may occur during Kangaroo care, if Kangaroo care is part of standard care. 32 to 35.99 weeks PMA -Cautious use of multimodal stimulation: This phase applies as soon as the infant demonstrates readiness to receive additional sensory stimulation. The therapist reviews infant engagement/disengagement cues with the caregiver, describes techniques used in multimodal stimulation [18], models the progressive sequence, and supports caregivers in implementing it themselves: (1) Swaddling Parents/caregivers: information about study; informed consent

Standard care
Referral to study by medical staff -Infants: born below 35 weeks GA; medically stable -Parents/caregivers: willingness to participate in MT, located within reasonable commuting distance from treating NICU

Not eligible
Do not consent and cradling infant statically (without tactile or vestibular stimulation at first).
(2) Commencing contingent singing/humming of simple melodies or modified songs of kin while cradling infant.
(3) Adding gentle massage while singing and cradling infant (delivered in cephalocaudal and proximodistal order [18]). (4) Gently rocking while providing massage, singing/humming, and cradling. (5) If the infant has begun opening his/her eyes, using vocal inflection to promote eye opening, eye contact, and responses to social cues (e.g., smiling, cooing). The sequence will be paced and modified according to infant engagement/disengagement cues, and will be reversed or paused in response to disengagement cues. From 36 weeks PMA -Engagement in musical exchange: This phase applies when the infant demonstrates readiness to engage in more interactive levels of musical exchange. Caregivers interact musically with the infant, using vocal inflection and sung cues to encourage the infant to achieve a quiet, alert state and engage in eye contact, vocalization, and rudimentary social interaction. Depending upon infant readiness, caregivers may use premature infant-friendly, basic musical toys to promote auditory localization, auditory tracking, visual tracking, eye contact, reaching, grasping, and mouthing. The therapist will encourage the caregiver to use preferred lullabies and children's songs or to modify songs of kin [21] in order to encourage musical dialogue with the infant. Standard care during NICU: This will vary across countries, but will typically include necessary medical care and a limited amount of interventions to reduce stress among infants and to inform and promote safety in parents [31]. MT post-discharge from hospital: Individual MT sessions will be offered, minimum 5 and maximum 7, 45minute sessions per infant/parent distributed across six months. These will occur at municipal child health centers or at home, and comprise: (1) Verbal greeting and brief discussion of infant's progress (approx. 5 min).
(3) Engagement in musical exchange following the procedures described in the "from 36 weeks" category above, with therapist modelling musical engagement (approx. 10 min). (4) Discussion of current infant/parent challenges and strategies for using musical interactions to address these needs, with therapist modelling musical techniques to promote self-regulation or to facilitate musical interaction, depending upon needs identified by the caregiver (approx. 10 min). (5) Caregiver demonstration of techniques discussed during session (approx. 10 min). (6) Musical closure and reminder of planned timing for next visit (approx. 5 min). Any siblings may be involved if desired by the caregiver. Subsequent sessions will follow a similar sequence, adjusted to infant developmental level and ongoing needs. The therapist will work in close dialogue with those providing standard aftercare procedures. Standard care post-discharge from hospital: This includes follow-up visits and preventive interventions in primary or specialist health care as needed. Preventive interventions during the first year of life are focused on growth/eating/nourishment as well as psychomotor/sensory development and also include a focus on families and bonding [31]. According to our user representative (see separate document), support on psychological issues may however be limited and sometimes insufficient or inadequate.

Outcomes
Outcomes will be assessed at several time points: at baseline; one to two days before discharge to home; at 6 months corrected age (end of MT; primary endpoint); and 12 months of corrected age (CA; chronological age reduced by number of weeks born preterm [30]). Data collectors and assessors will be trained in assessment procedures and blinded to participant allocation; success of blinding will be verified. Primary outcome: Bond between primary caregiver and infant will be evaluated at all time points (primary time point: 6 months CA) using the Postpartum Bonding Questionnaire (PBQ). PBQ is a self-rating screening instrument for disorders of the early mother-infant relationship consisting of 25 statements on a six-point Likert scale (each 0-5; sum score ranging from 0 to 125; high = problematic), addressing problems in the mother-infant relationship based on weakened bonding; rejection and anger; anxiety about care; and risk of abuse [32]. The scale is validated and widely used in clinical practice and research [33]. It has been translated and tested in several languages and cultures [34] and has high internal consistency [35] and testretest reliability [32], also in the Norwegian version [36].

Secondary outcomes:
(1) Infant development will be assessed blindly using the Bayley Scales of Infant and Toddler Development (BSID). It covers cognitive, language, and motor development and is considered the gold standard for assessing development of young and premature infants up to 42 months [37].
(2) Re-hospitalization during the first year of life (excluding outpatient visits), based on electronic health records: Safely bonded parents panic less when an infant develops fever and may be more capable of handling minor illnesses of their infants. A previous study [29] found a promising difference of 15% with music therapy compared to 30% with standard care.
(3) Infant socio-emotional development will be evaluated using the Ages and Stages Questionnaire Social-Emotional (ASQ:SE). This is a parent-completed questionnaire that targets social-emotional competence and problem behaviours, with 19 to 22 Likert-scaled items depending on child age [38,39].
(4) Infant social behaviour will be assessed using the Alarm Distress Baby Scale (ADBB) [40]. It covers facial expression, eye contact, general level of activity, self-stimulating gestures, vocalizations, response to stimulation, relationship. It has shown high sensitivity, specificity and reliability [40].
(5) Parental depression will be assessed with the Edinburgh Postnatal Depression Scale (EPDS). The 10item self-report instrument assesses caregiver's postpartum depressive symptoms, focusing specifically on more severe problems rather than those that are common to nearly all new mothers (such as loss of energy, feeling tired, changes in appetite and sexual drive). It has shown high sensitivity and specificity in two Norwegian studies [41,42].
(6) Level of parental stress will be assessed with the Parental Stress Scale (PSS). This is a self-report 18-item questionnaire that assesses stress levels associated with parenting [43].
(7) In addition, a checklist of medical and social factors will be completed at baseline and updated 1-2 days prior to discharge, to track the presence of particular factors that might impact infant responsiveness (e.g., intraventricular hemorrhage, presence and nature of sedation, abnormal hearing screening at discharge, etc.), or parental engagement (e.g., socioeconomic status, receiving treatment for mental health or substance use problems, etc.). Within the MT group, physiological signs (heart rate, respiratory rate and oxygen saturation) and behavior state will be informally monitored during the course of MT as part of the provision of infantdirected approaches. This part will also assess use and costs of medical services. Existing electronic health records will be used wherever possible to improve reliability and completeness and to reduce costs and burdens of data collection.

Cost-effectiveness:
We will collect the data that are necessary for analyzing cost-effectiveness both from a health services perspective (i.e. costs of all treatments incurred within the health sector) and from the broader societal perspective (i.e. including also indirect costs such as productivity losses). If clinical effectiveness is found, we will apply for separate funding to analyze incremental cost-effectiveness ratios and willingness to pay. Otherwise, these data will be used to describe the context in which the treatment took place.

Trial procedures, statistical considerations, and data management Randomization, allocation concealment and blinding:
After informed consent and baseline assessment, participants will be randomly assigned to NICU-MT or standard care using a computer-generated randomization list, with ratio 1:1, in blocks with sizes of 2 or 4 varying randomly, using email and an online system. The random allocation sequence will be generated and administered by people with no involvement in the clinical work to ensure allocation concealment. One day before discharge to home, participants will be randomized a second time to post-discharge MT or standard care in a 1:1 ratio, using the same procedures. This two-step randomization was chosen as the best way to create balance among those remaining in the study for the aftercare phase, and to avoid differential drop-out in the NICU phase due to expectations for the aftercare phase. In multiple pregnancies, only the first-born infant will be included and randomized, while remaining siblings will receive the same interventions for ethical and practical reasons. Blinding of interventions is not possible, but all outcomes that are not self-reports will be blinded, and success of blinding will be tested.

Power calculation and sample size:
No previous RCT examined effects of MT on the PBQ; two small RCTs included in our systematic review [25] and a recent non-randomized study [29] examined mother-infant bonding, but provided insufficient data for meta-analysis. Studies using the PBQ with other interventions found effects ranging from around 0.25 ([44], posttest) through 0.5 ( [45], mothers at 1/6 months), 1.4 ( [46], 4 months), 2 ( [45], fathers at 1/6 months), 9 ( [44], 3 months), with SDs ranging from 4 to 12. Assuming a difference of 4 points on the PBQ (SD = 8) as a minimal clinically important difference for this study, power of 80% will be achieved for each main effect (each tested on a two-sided 2.5% significance level, i.e. 5% with Bonferroni correction for two tests) with a sample size of 155. Taking into account some clustering by country (ICC 0.01; 5 countries), this is increased to 203. To allow for 20% attrition, we will aim to include 250 infants (50 in each country) and their parents. This sample size will also ensure power for testing proportion differences of about 15% (e.g. binary analysis of problematic bonding; re-hospitalization). Special considerations are needed for multiple pregnancies (twins, triplets, etc.), which account for about 2% in Hordaland [4], but are more common in NICUs due to their elevated risk of preterm birth. Including all siblings would serve to increase the sample size, but may lower the resulting power due to cluster effects. This interdisciplinary team, experienced in conducting high-quality RCTs in MT research, will be responsible for the overall conduct and integrity of the study. In addition to the three institutions above, the network of national and international partners includes a range of clinical, research, and user organizations. Recruitment strategy: The sites listed above vary between 13 and 60 beds and between 250 and 500 admissions per year. Following a pilot cohort at one site, an 18-month period for recruitment will be sufficient to achieve the targeted sample size. Each site will aim to recruit about 50 infants and their parents; therefore, slow recruitment at some sites will be tolerable. Recruitment rates will be monitored carefully. Local and national partners responsible for primary care provision, such as Bergen Municipality in the Bergen area, will serve as contact points after discharge and will be actively involved wherever possible.